Program in Pharmacology, Weill Cornell Graduate School of Medical Sciences, New York, New York 10065, USA.
Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
Cold Spring Harb Perspect Med. 2024 Aug 1;14(8):a041386. doi: 10.1101/cshperspect.a041386.
Metastasis is the ultimate and often lethal stage of cancer. Metastasis occurs in three phases that may vary across individuals: First, dissemination from the primary tumor. Second, tumor dormancy at the metastatic site where micrometastatic cancer cells remain quiescent or, in dynamic cycles of proliferation and elimination, remaining clinically undetectable. Finally, cancer cells are able to overcome microenvironmental constraints for outgrowth, or the formation of clinically detectable macrometastases that colonize distant organs and are largely incurable. A variety of approaches have been used to model metastasis to elucidate molecular mechanisms and identify putative therapeutic targets. In particular, metastatic dormancy has been challenging to model in vivo due to the sparse numbers of cancer cells in micrometastasis nodules and the long latency times required for tumor outgrowth. Here, we review state-of-the art genetically engineered mouse, syngeneic, and patient-derived xenograft approaches for modeling metastasis and dormancy. We describe the advantages and limitations of various metastasis models, novel findings enabled by such approaches, and highlight opportunities for future improvement.
转移是癌症的最终阶段,通常也是致命的阶段。转移发生在三个阶段,在个体之间可能有所不同:首先,从原发性肿瘤扩散。其次,转移部位的肿瘤休眠,微转移癌细胞保持静止,或者在增殖和消除的动态循环中,仍然无法临床检测到。最后,癌细胞能够克服微环境的限制以生长,或者形成临床上可检测到的播散转移,这些转移定植于远处器官,且在很大程度上是无法治愈的。已经采用了多种方法来模拟转移,以阐明分子机制并确定潜在的治疗靶点。特别是,由于微转移结节中癌细胞数量稀少,以及肿瘤生长所需的潜伏期较长,转移性休眠在体内建模具有挑战性。在这里,我们综述了用于模拟转移和休眠的最先进的基因工程小鼠、同种异体和患者来源的异种移植方法。我们描述了各种转移模型的优缺点、此类方法带来的新发现,并强调了未来改进的机会。